Uncouplers insecticides

Dinitrophenol is a member of the aromatic family of pesticides, many of which exhibit insecticide and fungicide activity. DNP is considered to be highly toxic to humans, with a lethal oral dose of 14 to 43mg/kg. Environmental exposure to DNP occurs primarily from pesticide runoff to water. DNP is used as a pesticide, wood preservative, and in the manufacture of dyes. DNP is an uncoupler, or has the ability to separate the flow of electrons and the pumping of ions for ATP synthesis. This means that the energy from electron transfer cannot be used for ATP synthesis [75,77]. The mechanism of action of DNP is believed to inhibit the formation of ATP by uncoupling oxidative phosphorylation. 

Dinitrophenols had been used as insecticides since 1892 but it was not until the 1930s that their value as herbicides was discovered and 4,6-dinitro-o-cresol (DNOC) was introduced. The trouble with dinitrophenols was their toxicity to all living organisms that respire. Their mode of action is through the uncoupling of oxidative phosphorylation, an effect that leads to a rapid death of any organism that comes into contact with the chemical, including the operator. 

A recently introduced insecticide/acaricide, chlorfenapyr (Figure 3.14), has been shown to disrupt the electrochemical gradient in mitochondria and, thereby, uncouple oxidative phosphorylation. There is also evidence that the compound is a pro-insecticide, being converted into the active form by mixed function oxidases within the insect or mite. 

The control of lice, mites and warbleflies continues to be achieved by the older agents. The selection pressure that caused resistance in cattle ticks and sheep blowfly has not been encountered by these other ectoparasites since their less frequent incidence has required less insecticide/acaricide usage. In addition to the OPs, rotenone (92) (the active principle of derris), an uncoupler of oxidative phosphorylation, continues to be used to combat mange. 

Over 200 organic insecticides, designed to kill insects without excessive danger to humans and animals, are presently in use/ Many of these compounds act by inhibiting cell respiration others uncouple ATP synthesis from electron transport. 

Ryania. The root and stem of the plant Ryania speciosa, family Flacourtiaceae, native to South America, contain from 0.16—0.2% of insecticidal components, the most important of which is the alkaloid ryanodine [15662-33-9], C25H3509N (8) (mp 219-220°C). This compound is effective as both a contact and a stomach poison. Ryanodine is soluble in water, methyl alcohol, and most organic solvents but not in petroleum oils. It is more stable to the action of air and light than pyrethrum or rotenone and has considerable residual action. Ryania has an oral LD5Q to the rat of 750 mg/kg. The material has shown considerable promise in the control of the European com borer and codling moth and is used as a wettable powder of ground stems or as a methanolic extract. Ryanodine uncouples the ATP—AD P actomyosin cycle of striated muscle. 

Chlorfenapyr (Phantom ), a trifluoromethyl-containing pyrrole ring insecticide, belongs to a new class of uncouplers of oxidative phosphorylation [80], The original insecticidal lead that resulted in chlorfenapyr was the fermentation product dioxapyrrolomycin, isolated from a Streptomyces strain [81], The presence of the trifluoromethyl group is essential for a broad spectrum of insecticide and acaricide activity. 

Hunt, D.A. and Tracy, M.F., Pyrrole insecticides A new class of agriculturally important insecticides functioning as uncouplers of oxidative phosphorylation, in Insecticides with novel modes of action, Ishaaya, I. and Degheele, D., Eds., Berlin Spriner-Verlag, 1998, p. 138. 

Tphe search for insecticides with modes of action different from the A well-known acetylcholinesterase inhibition led us to uncouplers of oxidative phosphorylation (1, 2). An inherent advantage of such pesticides would be the absence of cross-resistance with organophosphorus compounds and chlorinated hydrocarbons. The number of commercial pesticides which are likely to act by uncoupling of oxidative phosphorylation is small. All of them can be regarded as derivatives of the... 

From earlier work with benzimidazoles and several other types of NH acidic heterocycles we had learned (6) that by trying to use uncouplers as pesticides or more specifically as insecticides and acaricides, one has to cope with two problems. First, since mitochondrial phosphorylation is a ubiquitous process, both pests and mammals may be harmed secondly, the energy producing pathways in mitochondria and chloroplasts seem to be similar hence some of the uncouplers are also toxic to plants (7). 

Figure 2) (8). These compounds are generally much less toxic to mammals and less phytotoxic than the related dicyanocarbonylphenylhydra-zones investigated by DuPont workers several years ago (9). Some of our hydrazones (Figure 2) show interesting insecticidal and acaricidal properties (not discussed in detail here). Many are potent uncouplers of oxidative phosphorylation in rat liver mitochondria. 

The dinitrophenols were the first group of uncouplers to be commercialized, and representatives of this group have found use as herbicides, insecticides/ acaricides and fungicides. However, several have been superseded due to their toxicity and lack of selectivity. 

Based on the structure of dioxapyrrolomycin and related compounds, it was postulated that the insecticidal activity of these compounds was due to the uncoupling of oxidative phosphorylation. This was subsequently confirmed through mouse-liver mitochondrial assays [6]. 

Uncoupling activity is dependent on two physicochemical parameters (1) lipo-philicity (log P) that allows the molecule to move across the mitochondrial membrane [7, 8] and (2) acidity (pXa) that allows the molecule to disrupt the proton gradient necessary for the conversion of ADP into ATP [7-9]. Studies have shown that a log P of 6.0 + 1 and a pXa range of 7.0-7.9 are necessary for optimal insecticidal activity [10]. 

Several polyfluoroalkyl amine and aniline derivatives have been recently reported with either herbicidal (1-3) or insecticidal (4-8) utility. As lipophilic weak acids, their modes of action have been linked to uncoupling of mitochondrial oxidative phosphorylation which produces ATP in cells throughout the plant and animal kingdoms. Early in 1988, we reported that the perfluorinated carboxanilide EL-499 (1 2, Figure 1.) represents a novel class of soil insecticide derived from electrofluorination technology and is under investigation for the control of corn root worm larvae in corn. (8) In contrast with EL-499, normal chain perfluorinated carboxanilides were described as labile to mild hydrolytic conditions at room temperature and thus exhibited little acute larvicidal... 

Rotenone, the active ingredient of derris powder, an insecticide prepared from the roots of the leguminous plant Lonchocarpus nicou. It is an inhibitor of complex I (NADH — ubiquinone reduction). The same effect is seen in the presence of amytal (amobarbital), a barbiturate sedative drug, which again inhibits complex I. These two compounds inhibit oxidation of malate, which requires complex I, but not succinate, which reduces ubiquinone directly. The addition of the uncoupler... 

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